The behavioral abnormalities associated with schizophrenia are likely to involve pathological function of the limbic system. Functional and structural neuroimaging studies in the limbic region of schizophrenic brains have provided compelling evidence in support of this assertion. Ingestion of phencyclidine (PCP) or systemic injection of ketamine produces a syndrome that mimics the symptoms of acute schizophrenic psychosis. These pharmacological observations raise the possibility that a decrease of normal NMDA receptor (NMDAR) function can elicit psychotic symptoms similar to those suffered by schizophrenic patients. Recently, Mohn, et al (1999) describe a transgenic mouse model of schizophrenia, a partial knock out of the NR1 subunit of the NMDAR (5% expression), with behavioral deficits such as increased motor activity, stereotype and deficits in social and sexual interactions. This partial "knock down" of NR1 expression is rescued by haloperidol and clozapine. However, the mechanism(s) of action of decreased NMDA- receptor function that result in the observed deficits in information processing integral to the syndrome of psychosis have been little investigated. Our findings have lead to the following hypotheses: the psychotogenic action of NMDA antagonists may be attributed to selective blockade of the NMDA-dependent drive of inhibitory circuits (Grunze). The decreased excitatory drive of interneurons disrupts network function so that abnormal information processing consistent with cognitive deficits associated with psychosis, ensues. In particular, [Specific Aim I] it is hypothesized that the EPSP of CAL interneurons has a significant NMDA-dependent component that is larger than the NMDA component of the feedforward Schaffer collateral input to CA1 pyramidal neurons, and/or EPSC is more sensitive to NMDA antagonists. Accordingly, NMDAR antagonists have a selectively greater effect on the EPSP's of interneurons (in the CA1 region of the hippocampus the EPSP's and EPSC's that we will test, original from either feed-forward-CA3-or feed- backward-CA1-input or from both) compared EPSC's of projection cells. Pathological NMDAR hypofunction could result from multiple mechanisms, including but not limited to 1) factors affecting NMDAR- binding to glutamate; 2) factors affecting NMDAR-associated channel activity; 3) factors affecting downstream mechanisms associated with NMDAR activation (for example those linked to the NMDA-associated PSD-complex). We plan to examine the first of these mechanisms. We [Specific Aim 4a] hypothesize that an endogenous compound, N-acetyl- aspartylglutamate (NAAG), has NMDAR antagonist activity and can selectively block the NMDAR-component of EPSC's on interneurons in the CA1 region of the hippocampus. We further [Specific Aim 4b] hypothesize that the turnover of NAAG is sufficiently high that inhibition of NAAG's catabolic enzyme will block the NMDAR-component of EPSC's and exposure to a soluble form of these catabolic enzyme [Specific Aim 4c] will enhance the NMDAR-component by decreasing endogenous NAAG. Our preliminary data demonstrates that inhibition of GCP II increases endogenous NAAG sufficient to significantly reduces NMDAR synaptic activation in CA1 pyramidal cells and interneurons in the hippocampal slice, probably as a result of the high rate of turnover of NAAG in vitro. The effects on NMDAR activity of a knockout of the GCP III gene are hard to predict in part because: 1) the mechanisms responsible for the rate of production of the NAAG mediating this response are unknown; 2) NMDAR activity in response to a chronic increase in NAAG is unknown. Nevertheless, a state of chronic NMDAR hypofunction is a distinct possibility that, in consideration of its association with psychosis ought to be examined as a first step towards the phenotypic characterization of these animals. We [Specific Aim 5] hypothesize that NMDAR function will be reduced in the CA1 region of the hippocampi of GCP II knockout mice compared to wild type mice. If true, thee ko mice may serve in behavioral studies of NMDAR hypofunction in the development and maintenance of place (or other specific associations) hippocampal cells.